Alpha-alkyl polyolefinic carboxylic acids and derivatives thereof useful in the treatment of psoriasis and allergic responses

ABSTRACT

Polyolefinic compounds represented by the general formula ##STR1## in which R and R 1  are each hydrogen or an alkyl group of from 1 to 5 carbon atoms; R 2  is an alkyl group of from 1 to 5 carbon atoms; R 3  is hydroxyl, alkoxy of from 1 to 5 carbon atoms, NH 2 , NHR 2  or NR 2  R 2  and Z is a cycloalkyl, cycloalkenyl or cycloalkdienyl group substituted with from 0 to 5 alkyl groups, a keto group or a hydroxyl group or a phenyl group substituted with from 0 to 4 hydroxy, alkoxy, alkyl or trifluoromethyl groups or halogen atoms or combinations thereof and the pharmaceutically-acceptable salts thereof. 
     The foregoing compounds have been found to be effective in the treatment of psoriasis, inflammatory conditions and allergic responses.

BACKGROUND OF THE INVENTION

This is a continuation-in-part application of application Ser. No.511,822, filed July 8, 1983, U.S. Pat. No. 4,505,930 which in turn is acontinuation-in-part application of application Ser. No. 392,837, filedJune 28, 1982 and issued as U.S. Pat. No. 4,472,430 on September 18,1984.

The present invention relates to novel alpha-alkyl polyolefiniccarboxylic acids derived from such polyolefinic intermediates asretinal(3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenal;vitamin A aldehyde) which possesses the structure ##STR2##

A synthesis of retinal from beta-ionone and propargyl halide isdescribed in U.S. Pat. No. 3,060,229.

A number of alpha-substituted polyolefinic carboxylic aldehydes, acidsand esters are described in the scientific literature. Japanese patent10,124 (1964); C.A. 62, 2798 g (1965) describes2,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenonicacid and2,7,11-trimethyl-13-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10,12-tridecahexanenoicacid; Machleidt, et al., Justus Liebigs Ann. Chem., 679,20 (1964)describes α-fluoropolyolefinic acids and esters; Chan, et al., J.A.C.S.96, 3642 (1974) describe polyolefinic carboxaldehydes; Haeck, et al.,Recuil 85 (1966) pp. 334-338 describe5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid and corresponding 2,4,6,8,10,12-tridecahexanenoic acids as well asthe corresponding α-cyano and α-carboxy substituted compounds. Buchta,et al., Naturwissenschaften 46, 74 (1959) describemethyl-2-methyl-7-phenyl)-2,4,6-heptatrienoate.

SUMMARY OF THE INVENTION

The present invention is directed to novel alpha-alkyl, polyolefiniccarboxylic acids and derivatives thereof of the general formula ##STR3##in which R and R₁ are each hydrogen or an alkyl group of from 1 to 5carbon atoms; R₂ is an alkyl group of from 1 to 5 carbon atoms; R₃ ishydroxyl, alkoxy of from 1 to 5 carbon atoms, NH₂, NHR₂ or NR₂ R₂ and Zis a cycloalkyl, cycloalkenyl or cycloalkdienyl group substituted withfrom 0 to 5 alkyl groups, a keto group or a hydroxyl group, or a phenylgroup substituted with from 0 to 4 hydroxy, alkoxy, alkyl ortrifluoromethyl groups or halogen atoms or combinations thereof; and thepharmaceutically-acceptable salts thereof. The invention includescompounds wherein the double bonds are in the cis or transconfiguration.

The foregoing compounds have been found to be effective in the treatmentof psoriasis, acne, and cellular and humoral immunodeficiancy.

Compounds of the foregoing invention have also been found active inregulating the formation of lipoxygenase and as such possess therapeuticvalue in the treatment of inflammatory conditions and allergicresponses.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

A preferred group of compounds within the aforesaid general formula arethose in which R₁ is methyl, R₃ is hydroxyl or alkoxy of from 1 to 5carbon atoms and Z is a cycloalkenyl group substituted with from 0 to 3alkyl groups, or a phenyl group substituted with from 1 to 4 alkoxy oralkyl groups containing up to 5 carbon atoms or combinations of theforegoing, including those compounds in which one or more of the doublebonds are in the cis configuration. Within this preferred group ofcompounds, still more preferred are compounds in which Z is the group2,6,6-trimethyl-1-cyclohexen-1-yl. An especially preferred compound is2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid ##STR4##

The compounds of this invention can be prepared from known polyolefinicmaterials, e.g., retinal, employing known synthetic procedures of fromanalogous polyolefinic compounds which can be prepared in accordancewith methods known by those skilled in the art.

For example, employing retinal as starting compound, condensationthrough the aldehyde group with the active methylene group of suitableacids or acid derivatives of the formula: ##STR5## will result in thecorresponding undecapentaenoic acid derivative. Activating substituentson the alpha carbon atom of the said compounds, e.g., trialkylphosphonoderivatives, facilitate the condensation reaction.

The condensation reaction is usually carried out by reacting theselected starting materials in a suitable solvent preferably in thepresence of a strong base such as sodium hydride, sodamide, sodiumethoxide and similar alkali metal compounds. The reaction is usuallyexothermic and is consequently cooled to control the rate of reaction.After the initial reaction has subsided, the reaction mixture is heatedat reflux to assure completeness of reaction.

A variety of reaction solvents can be employed including dioxane,tetrahydrofuran (THF), dimethylformamide, dimethylacetamide and similarwater-miscible organic solvents. The solvents employed are preferablyanhydrous, particularly when the alkali metal bases are used, to avoidsecondary reactions.

The present new compounds can also be prepared from correspondingcompounds containing only alpha hydrogen by alkylation using alkylatingagents such as dialkyl sulfates, e.g., dimethyl and diethyl sulfate andalkyl halides, e.g., propyl bromide and ethyl bromide, in the presenceof alkali metals or alkali metal compounds which react with alphahalogen, e.g., sodium hydride, lithium, potassium, sodamide and alkalimetal alkoxides such as sodium or potassium ethoxide.

The compounds of this invention are also prepared by partial reductionof corresponding compounds containing acetylenic in lieu of ethylenicbonds. In addition, the dehydrohalogenation of corresponding alpha-haloacid with no ethylenic bond between alpha and beta carbon atoms alsoleads to the present compounds.

A further preparative method involves condensation of appropriate sidechains with the appropriate side chains with the appropriatelysubstituted cyclohexanone with, for example, anomegahaloundecapentaenoate, preferably in the form of the correspondingGrignard reagent, followed by hydrolysis of the product to form theα-substituted cyclohexanol and then dehydration to the cyclohexenylcompound. The side chain, i.e., the eleven carbon side chain can beformed piecemeal by suitable condensation employing the half aldehyde ofa dicarboxylic acid of suitable carbon content to condense with a sidechain of suitable carbon content with groups suitable to react with thealdehyde functional group.

A still further process can be used involving oxidation of derivativesof the desired undecapentaenoic acid with mild oxidants such ashypochlorite, e.g., sodium hypochlorite. The oxidants selected shouldpreferably avoid secondary reactions with the remainder of the substratemolecule, or the oxidation should be carried out under controlledconditions to avoid appreciable secondary reactions, as by conductingoxidation with hypochlorite solution at or below about 10° C. andpreferably between 0° and 5° C. For example, a compound of the formula##STR6## on oxidation with hypochlorite yields the corresponding acid offormula I herein. These new compounds can also be prepared bydehydration of corresponding α or β hydroxy acids or esters to form analpha-beta ethylenic bond. The beta hydroxy acids or esters can beformed by condensation of an alpha-halo-carboxylic acid (or ester) withan aldehyde of two carbons less than the desired side chain in thepresence of zinc (the Reformatsky Reaction).

The present compounds can also be prepared by oxidation of thecorresponding aldehyde and alcohol of the same carbon content usingoxidizing agents known for such reaction, e.g., hypochlorite, aspreviously described.

EXAMPLE 1 Ethyl2,5,9-Trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10,-undecapentaenoate##STR7##

Sodium hydride (4.03 g, 50%) dispersion in mineral oil) was washed withdry pentane three times and suspended in 50 ml of anhydrous THF undernitrogen. The stirred mixture was cooled in an ice-water bath and 20.6 gof triethyl 2-phosphonopropionate was added dropwise. The resultingmixture was stirred for additional two hours while allowing the reactionmixture to warm up slowly to room temperature. The mixture was thencooled in an ice-water bath and a solution of retinal (16 g) in 50 ml ofanhydrous THF was added dropwise. The resulting dark red mixture wasstirred for four hours at room temperature; 700 ml of cold water wasadded and the mixture was extracted with three 200-ml portions of ether.The combined ethereal solution was washed with 100 ml of water and driedover sodium sulfate. Removal of solvent gave the crude ester (20 g, 97%)as a dark red oily substance. This material was used for the preparationof the free acid of Example 2 without further purification.

EXAMPLE 22,5,9-Trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-UndecapentaenoicAcid ##STR8##

The crude ethyl ester (20 g) from Example 1 was dissolved in 50 ml ofethanol and a solution of potassium hydroxide (5.12 g) in 45 ml ofethanol and 5 ml of water was added dropwise with stirring undernitrogen. The resulting mixture was stirred for 12 hours at roomtemperature. The reaction mixture was partially concentrated underreduced pressure and then mixed with 500 ml of water. The resultingmixture was extracted with three 150 ml portions of ether. The ethereallayer was discarded, the aqeuous layer was acidified to pH 3 with 10Naqueous hydrochloric acid. The resulting product was extracted intoether. The etheral solution was washed with water and dried over sodiumsulfate. Concentration and filtration of this solution afforded thedesired product as orange-red powders. Recrystallization inacetone/ethanol gave 9.3 g (50.6%) of pure product, mp 197°-199° C., UVspectrum (methanol) max 380 nm.

In like manner to the procedure described in Examples 1 and 2, thefollowing compounds were prepared:

Ethyl 2-ethyl-5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen1-yl)-2,4,6,8,10-undecapentaenoate (an oil);

Ethyl-2-propyl-5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoate(an oil);

2-Ethyl-5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)2,4,6,8,10-undecapentaenoicacid (m.p. 162°-165° C.);

2-Propyl-5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid (m.p. 172°-175° C.).

EXAMPLE 3A Triethyl 2-Phosphonobutyrate ##STR9##

A mixture of ethyl 2-bromobutyrate (100 g, 0.5/mole and triethylphosphite (85.2 g, 0.5/mole) was heated in an oil bath at 145° C. for 2hrs. After cooling to room temperature, the reaction mixture wasdistilled at atmospheric pressure to remove the bulk of the ethylbromide. The desired product was then distilled at 80°-95° C. (0.15 mmof Hg). Obtained: 60 g of triethyl 2-phosphonobutyrate as colorlessclear liquid.

EXAMPLE 3B5,9-Dimethyl-2-Ethyl-11-(2.6,6-Trimethyl-1-Cyclohexen-1-yl)2,4,6,8,10-UndecapentaenoicAcid ##STR10##

In analogy to the procedure given in Example 1: Triethyl2-phosphonobutyrate was reacted with retinal to give ethyl5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoate,which was converted by the procedure of Example 2 to5,9-dimethyl-2-ethyl-11(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid, m.p.=164°-165° C.

EXAMPLE 4A Triethyl 2-Phosphonovalerate ##STR11##

In analogy to the procedure given in Example 3: Ethyl 2-bromovaleratewas treated with triethylphosphite to give triethyl 2-phosphonovalerateas a colorless clear liquid, b.p.=95°-110° C. (0.175 mm of Hg).

EXAMPLE 4B5,9-Dimethyl-11-(2,6,6-Cyclohexen-1-yl)-2-Propyl-2,4,6,8,10-UndecapentaenoicAcid ##STR12##

In analogy to the procedure described in Example 1: Triethyl2-phosphonovalerate was reacted with retinal to give ethyl5,9-dimethyl-11-(2,6,8-cyclohexen-1-yl)-2-propyl-2,4,6,8,10-undecapentaenoate,which was converted by the procedure of Example 2 to5,9-dimethyl-11-(2,6,6-cyclohexen-1-yl)-2-propyl-2,4,6,8,10-undecapentaenoicacid, m.p.: 172°-175° C.

The compounds of this invention are active against various skindisorders, such as acne and psoriasis, when tested according to modelsconsidered to be predictive of the clinical condition in humans. Themodels used were the rhino mouse procedure (Kligman, et al., J.Investigative Dermatology 73, 354 (1979)), the rabbit comedolyticprocedure (Mills OH, Kligman AM: Assay of Comedolytic Agents in theRabbit Ear, Animal Models in Dermatology; Relevance to HumanDermatopharmacology and Dermatotoxicology, edited by H. I. Maibach, NewYork Churchill-Livingston, 1975, pp. 176°-183°) and the mouse epidermalcell culture procedure (Marcelo, et al., J. Cell Biol., 79, 356 (1978).Testing was done comparatively against standard retinoids known to beeffective in these disorders and against a known α-methyl retinoid(2,7-dimethyl-9-2,6,6-trimethyl-1-cyclohexene-1-yl-2,4,6,8-nonatetraenoicacid, referred to as DTCNA).

Activity equal to or greater than the standards and the known compoundwas shown by 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexene-1-yl)-2,4,6,8,10-undecapentaenoic acid (TTCUA). Thus, in the rabbit earmodel at a concentration of 0.05%, it was equal to trans retinoic acid(TRA) in ability to reduce comedone size. In the rhino mouse model atthe same concentration, it was equal to TRA in ability to reducesignificantly the size of utriculi (pseudocomedones) and the amount ofhorny impaction in the utriculi. The skin of these mice showed moderateepidermal hyperplasia and significantly less wrinkling than theuntreated control animals.

In the mouse epidermal cell culture at a concentration of 12 ug/ml, itreduced cell proliferation, as measured by inhibition of the uptake oftritiated thymidine into DNA. Table I shows percentage uptake relativeto vehicle control (100%).

                  TABLE 1                                                         ______________________________________                                        Day of Culture                                                                Exposure to Drug                                                                           TRA    CRA      TTCUA  DTCNA                                     ______________________________________                                        3            77     47       31     53                                        5            53     75       15     61                                        10           36     64       21     60                                        ______________________________________                                    

Percentage uptake with TTCUA is seen to be up to five fold less at alltime points in comparison to both standards. Known compound DTCNA incontrast is seen to give about the same percentage uptake as thestandard drugs at all three time points. Likewise TTCUA showed highanti-differentiation activity at 12 ug/ml in the mouse epidermal cellculture, as shown in Table II.

                  TABLE II                                                        ______________________________________                                        Day of Culture                                                                           Vehicle                                                            Exposure to Drug                                                                         Control  TRA    CRA   TTCUA  DTCNA                                 ______________________________________                                        3          3/6      3/5    2/7   2/6    3/6                                   6          3/5      3/5    2/7   0.5/8.5                                                                              2/6                                   10         7.5/2    2/6      2/6.5                                                                               1/7.5                                                                              2/5                                   ______________________________________                                    

The ratios in the table represent scoring of two measured parameters,culture staining by the Kreyberg technique (maximum differentiation 10)and nuclei enumeration (maximum differentiation 0). Thus the highestpossible anti-differentiative activity would be given by the ratio 0/10.TTCUA is seen to be more active in both parameters than the twostandards whereas the known compound is about the same as the standards.

Compounds of the present invention were found to have potent activity inregulating the formation of lipoxygenase and as such possess therapeuticvalue in the treatment of inflammatory conditions and allergic responsessuch as anaphylaxis and asthma.

Lipoxygenases in mammals have been found in the lung, platelets, andwhite cells. They are enzymes capable of oxidizing arachidonic acid intohydroperoxyeicosatetraenoic acids (HPETEs) and their stable productshydroxyeicostetraenoic acids (HETEs). Lipoxygenases are classifiedaccording to the position in the arachidonic acid which is oxygenated.Platelets metabolize arachidonic acid to 12-HETE, whilepolymorphonuclear leukocytes contain 5 and 15 lipoxygenases. It is knownthat 12-HETE and 5, 12-diHETE are chemotactic for human neutrophils andeosinophils, and may augment the inflammation process. 5-HPETE is knownto be a precursor of slow-reacting substance of anaphylaxis (SRS-A). TheSRS family of molecules, such leukotrienes B, C, and D, have been shownto be potent bronchoconstrictors (see, NATURE 288, 484-486 (1980)).

The following protocol describes an assay to detect inhibitors of thelipoxygenase pathway. Such inhibitors are believed to be capable ofmodulating the biosynthesis of the leukotrienes, a property believed tobe useful in treating asthma and inflammatory disease states.

PROTOCOL

A homogenate of human neutrophils containing lipoxygense activity isincubated for 5 minutes at 37° with ¹⁴ C-arachidonic acid (AA). CitricAcid (2M) is used to quench the reaction. Following the addition of atrace amount of ³ H-AA together with an excess of unlabeled AA to eachtube, the mixture is extracted with chlorform/methanol. The organiclayer is washed with dilute acid and an aliquot is transferred to glasstubes and dried. The residue is dissolved in a small volume ofchloroform and an aliquot is spotted on silica gel TLC sheets. Thesheets are developed with an ethyl acetate/isooctane/water/acetic acidsolvent system. The AA-spots are identified with iodine vapors, cut outand placed in scintillation vials for counting. After adjusting for theextraction efficiency, the amount (pmole) of ¹⁴ C-AA in each of thetubes is quantitated. The pmoles of oxidized AA are obtained bysubtracting the pmoles of AA remaining in the tubes containing activeenzyme (control) from the pmoles of AA in the tubes acidified prior tothe addition of enzyme (blank). The ability of the test compounds tomodulate the activity of this enzyme is determined by an increase ordecrease in the net amount of AA oxidized.

A representative compound of the invention ##STR13## was found torequire a concentration of 13 μM (I₅₀ =13 μM) to inhibit 50% of theenzyme.

The therapeutic agents of this invention may be administered alone or incombination with pharmaceutically-acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form oftablets or capsules containing such excipients as starch, milk, sugar,certain types of clay and so forth. They may be administered orally inthe form of solutions which may contain coloring and flavoring agents orthey may be injected parenterally, that is intramuscularly,intravenously or subcutaneously. For parenteral administration, they maybe used in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic. Whenapplied topically for treating skin disorders, the present new productscan be provided in the form of dusting powders, aerosol sprays,ointments, aqueous compositions including solutions and suspensions,cream lotions and the like. In this regard, any of the commonly employedextending agents can be used depending on the nature of the product asis well-known in the art.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the particular patient under treatment. He will generallywish to initiate treatment with small dosages substantially less thanthe optimum dose of the compound and increase the dosage by smallincrements until the optimum effect under the circumstances is reached.It will generally be found that when the composition is administeredorally, larger quantities of the active agent will be required toproduce the same effect as a smaller quantity given parenterally.

A convenient form for administration of the present new compounds aresalts of those compounds in which R₃ is OH, particularly salts withalkali metals such as sodium and potassium, the ammonium salt and saltswith organic amines, particularly those commonly employed inpharmaceutical formulations. The salts, of course, should bepharmaceutically-acceptable, that is the salt formation does notappreciably increase the toxicity of the therapeutic agent nor cause atoxic reaction in the host.

What is claimed is: 1.2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid.
 2. A therapeutic composition for the treatment of psoriasis in ahuman host which comprises, in combination with at least onepharmaceutically acceptable extender, an effective amount for thetreatment of psoriasis of the compound2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid.
 3. A method for treating psoriasis in a human host which comprisesadministering to said host a therapeutically effective amount for thetreatment of psoriasis of the compound2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoicacid.